This research project is a joint effort by laboratories at the Chinese Academy of Sciences in Shanghai and Drexel University in Philadelphia to pursue the development of new classes of HIV-1 inhibitors targeting cell entry and to investigate the underlying hypothesis that antagonists of HIV-1 Env and host cell co-receptors can be combined in synergistic combinations to improve antiviral activity and decrease the susceptibility to function-compromising viral resistance. New agents for HIV-1 intervention remain urgently needed to reduce the effects of the global occurrence and spread of AIDS. HIV-1 infection of host cells is initiated by the interaction of the Env protein complex on the exposed surface of the virus with two cell receptors, CD4 and a co-receptor that is most commonly CCR5 and CXCR4. In our collaborating laboratories, we have been investigating new peptide triazole gp120 antagonists that can inactivate the virus and both CCR5 and CXCR4 co-receptor antagonists. Prior studies and our own preliminary results suggest that coordinately acting inhibitors targeting Env and co-receptor can improve the potential use of these types of inhibitors in prevention and therapeutic intervention. The phenomenon of synergy for these entry inhibitors needs to be better understood as it occurs during virus-host encounter, and maximally active synergy partners need to be identified. In this project, we will design new and potent antagonists of HIV-1 cell entry, including covalent fusions of inhibitors being developed in our collaborating research groups. Furthermore, we will seek to identify improved-activity synergistic combinations, evaluate mechanistic properties underlying the synergy, define the potential for antiviral synergy in different cellular environments, and evaluate the ability of the synergistic combinations to avoid virus mutagenic escape. This project will foster research in the scientific environments of both the Chinese Academy of Sciences and Drexel University on HIV-1 inhibitor design and mechanism studies. The collaboration supported through this project will be further enhanced by a translational program being established between the respective institutions, and the project in turn will help drive translational collaborations between the institutions.